Treatment of allergic symptoms with propanone derivatives

ABSTRACT

New propanone derivatives, useful for treating allergic diseases, the pharmacologically allowable salts thereof, their manufacturing process and pharmaceutical composition containing at least one of them as the active ingredient.

This is a Continuation in Part of Ser. No. 13,887 Filed Feb. 22, 1979,now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to new propanone derivatives, thepharmacologically allowable salts thereof, their manufacturing processand pharmaceutical composition containing at least one of them as theactive ingredient.

It is known that a so-called "chemical mediator", i.e., biochemicalsubstance in a living body such as histamine, serotonin, bradykinin,acetylcholine or SRS-A plays an important role in the appearance ofvarious allergic symptoms in the human body.

Thus something which antagonizes such biochemical substance and/orinhibits its release would be useful for treating allergic diseases andfrom this standpoint, various compounds have been synthesized andclinically tried so far.

Discovering that a certain propanone derivative exhibits a prominentanti-SRS-A effect, inhibitory effect on histamine release, inhibitoryeffect on experimental atopic asthma and/or inhibitory effect on homoPCA reaction, the present inventors have accomplished the presentinvention.

The object of the present invention is to offer new propanonederivatives useful for treating allergic diseases. Another object of thepresent invention is to offer the manufacturing process of thisderivative. Still another object of the present invention is to offerpharmaceutical composition containing at least one of the compoundsaccording to the present invention as the active ingredient and to givedirections to use this pharmaceutical composition.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 and 2 are diagrams illustrating the relation between theconcentration of compounds according to the present invention and theinhibitory effect on histamine release.

SUMMARY OF THE INVENTION

The compounds according to the present invention include propanonederivative of the general formula (I): ##STR1##wherein A isnon-substituted aryl group or aryl group substituted by hydroxyl group,lower alkoxy group or halogen, or non-substituted benzo[b]thienyl groupor benzo[b]thienyl group substituted by hydroxyl group, lower alkylgroup, lower alkoxy group, aryl group or halogen, B is di- loweralkylamino group or heterocyclic group which contains at least onenitrogen atom and may be substituted by lower alkyl group or aralkylgroup; however, when A is p-methylphenyl group, B denotes a group otherthan piperidino group, and R¹ is hydrogen, lower alkyl group or arylgroup, and the pharmacologically allowable salts thereof.

As evident from the results of pharmacological tests later to bedescribed,the compounds according to the present invention exhibit aprominent anti-SRS-A effect, inhibitory effect on histamine release,inhibitory effect on experimental atopic asthma and/or inhibitory effecton homo PCA reaction; and accordingly they are useful for treatingallergic diseases such as bronchial asthma, allergic rhinitis andallergic dermatitis.

Among the above compounds, pharmacologically preferable compounds areones expressed by the above-mentioned general formula (I) wherein A isnon-substituted phenyl group or phenyl group substituted by more thanone,preferably one or two groups; or naphthyl group, tetrahydronaphthylgroup, indanyl group or benzo[b]thienyl group non-substituted orsubstituted by one or two groups; said substituent being one selectedfrom lower alkyl group, lower alkoxy group, aryl group, hydroxyl groupand halogen, B is di- lower alkylamino group, or pyrrolidino group,piperidino group, piperazino group or morpholino group non-substitutedor substituted by lower alkyl group or aralkyl group, and R¹ ishydrogen, methyl, ethylor phenyl group, and their pharmacologicallyallowable salts.

Such preferable compounds include specifically; for instance,2-methyl-3-dimethylamino-1-tolylpropanone,2-methyl-3-diethylamino-1-tolylpropanone,2-methyl-3-dipropylamino-1-tolylpropanone,2-methyl-3-dimethylamino-1-xylylpropanone,2-methyl-3-pyrrolidino-1-tolylpropanone, 2-methyl-3-(methyl-substitutedpiperidino)-1-tolylpropanone, 2-methyl-3-piperidino-1-xylylpropanone,2-methyl-3-(methyl-substituted piperidino)-1-xylylpropanone,2-methyl-3-(4-methylpiperazino)-1-tolylpropanone,2-methyl-3-(4-methylpiperazino)-1-xylylpropanone,2-methyl-3-(4-ethylpiperazino)-1-tolylpropanone,2-methyl-3-(4-isopropylpiperazino)-1-tolylpropanone,2-methyl-3-(4-isobutylpiperazino)-1-tolylpropanone,2-methyl-3-(4-benzylpiperazino)-1-tolylpropanone,2-methyl-3-(4-ethylpiperazino)-1-(ethyl-substituted phenyl)propanone,2-methyl-3-(4-ethylpiperazino)-1-(ethyl-methylphenyl)propanone,2-methyl-3-morpholino-1-tolylpropanone,2-methyl-3-piperidino-1-(butylphenyl)propanone,2-methyl-3-piperidino-1-(hexylphenyl)propanone,2-methyl-3-piperidino-1-(hydroxyphenyl)propanone,2-methyl-3-piperidino-1-(methoxyphenyl)propanone,2-methyl-3-piperidino-1-(dimethoxyphenyl)propanone,2-methyl-3-piperidino-1-(ethoxyphenyl)propanone,2-methyl-3-piperidino-1-(propoxyphenyl)propanone,2-methyl-3-piperidino-1-(hydroxy-methoxyphenyl)propanone,2-methyl-3-piperidino-1-biphenylylpropanone,2-phenyl-3-piperidino-1-(methoxyphenyl)propanone,2-methyl-3-dimethylamino-propionaphthone,2-methyl-3-diethylaminopropionaphthone,2-methyl-3-dimethylamino-1-(methyl-substituted naphthyl)propanone,2-methyl-3-pyrrolidino-propionaphthone,2-methyl-3-(4-methylpiperazino)propionaphthone,2-methyl-3-piperidino-propionaphthone, 2-methyl-3-(methyl-substitutedpiperidino)propionaphthone, 2-methyl-3-piperidino-1-(methyl-substitutednaphthyl)propanone, 2-methyl-3-piperidino-1-(hydroxy-substitutednaphthyl)propanone, 2-methyl-3-piperidino-1-(methoxy-substitutednaphthyl)propanone, 2-methyl-3-piperidino-1-(ethyl-methoxy substitutednaphthyl)propanone, 2-methyl-3-piperidino-1-(ethoxy-substitutednaphthyl)propanone, 2-methyl-3-morpholino-propionaphthone,2-methyl-3-piperidino-1-(ethyl-substituted naphthyl)propanone,2-methyl-3-piperidino-1-(chloro-substituted naphthyl)propanone,2-methyl-3-piperidino-1-(chloro-methyl-substituted naphthyl)propanone,2-methyl-3-piperidino-1-(bromo-substituted naphthyl)propanone,3-piperidinopropionaphthone,2-methyl-3-piperidino-1-(5,6,7,8-tetrahydronaphthyl)propanone,2-methyl-3-(methyl-substitutedpiperidino)-1-(5,6,7,8-tetrahydronaphthyl)propanone,2-methyl-3-piperidino-1-(methyl-substituted-5,6,7,8-tetrahydronaphthyl)propanone,2-methyl-3-piperidino-1-(dimethyl-substituted5,6,7,8-tetrahydronaphthyl)propanone,2-methyl-3-piperidino-1-benzo[b]thienylpropanone,2-methyl-3-(methyl-substituted piperidino)-1-benzo[b]thienylpropanone,2-methyl-3-piperidino-1-(methyl-substituted-benzo[b]thienyl)propanone,3-piperidino-1-(dimethyl-substituted phenyl)propanone,2-methyl-3-piperidino-1-(diethyl-substituted phenyl)propanone,2-methyl-3-piperidino-1-(propyl-substituted phenyl)propanone,2-methyl-3-piperidino-1-(trimethyl-substituted phenyl)propanone,2-methyl-3-piperidino-1-(pentamethyl-substituted phenyl)propanone,2-methyl-3-piperidinopropiophenone, 2-methyl-3-(benzyl-substitutedpiperidino)propionaphthone, 2-ethyl-3-piperidinopropionaphthone,2-methyl-3-piperidino-1-indanylpropanone,3-piperidino-1-(methoxy-substituted naphthyl)propanone,3-piperidino-1-(hexyl-substituted phenyl)propanone,3-piperidino-1-(heptyl-substituted phenyl)propanone,3-piperidino-1-(octyl-substituted phenyl)propanone,3-piperidino-1-(decyl-substituted phenyl)propanone,2-methyl-3-piperidino-1-(heptyl-substituted phenyl)propanone,2-methyl-3-piperidino-1-(octyl-substituted phenyl)propanone,2-methyl-3-piperidino-1-(decyl-substituted phenyl)propanone,2-methyl-3-piperidino-1-(chloro-methoxy-substituted phenyl)propanone,2-methyl-3-piperidino-1-(dichloro-substituted phenyl)propanone,2-methyl-3-piperidino-1-(isopropyl-substituted phenyl)propanone,2-methyl-3-piperidino-1-(isobutyl-substituted phenyl)propanone,2-methyl-3-piperidino-1-(tert-butyl-substituted phenyl)propanone,2-methyl-3-dimethylamino-1-(methoxy-substituted naphthyl)propanone,2-methyl-3-(methyl-substituted piperidino)-1-(methoxy-substitutednaphthyl)propanone and 2-phenyl-3-piperidino-1-tolylpropanone; andpharmacologically allowable salts of these compounds.

More preferable compounds are;

2,4'-dimethyl-3-dimethylaminopropiophenone,2,4'-dimethyl-3-diethylaminopropiophenone,2,4'-dimethyl-3-morpholinopropiophenone,2,4'-dimethyl-3-pyrrolidinopropiophenone,2,4'-dimethyl-3-(4-methylpiperazino)propiophenone,2,4'-dimethyl-3-(4-ethylpiperazino)propiophenone,2,4'-dimethyl-3-(4-isobutylpiperazino)propiophenone,4'-methoxy-2-methyl-3-piperidinopropiophenone,4'-ethoxy-2-methyl-3-piperidinopropiophenone,2-methyl-3-piperidino-β-propionaphthone,2-methyl-3-dimethylamino-β-propionaphthone,2-methyl-3-morpholino-β-propionaphthone,2-methyl-3-pyrrolidino-β-propionaphthone,2,3',4'-trimethyl-3-piperidinopropiophenone,3',4'-dimethoxy-2-methyl-3-piperidinopropiophenone,2,4'-dimethyl-3-(4-benzylpiperazino)propiophenone,4'-methoxy-2-phenyl-3-piperidinopropiophenone,4'-hydroxy-2-methyl-3-piperidinopropiophenone,4'-hydroxy-3'-methoxy-2-methyl-3-piperidinopropiophenone,2-methyl-3-piperidino-α-propionaphthone,2-methyl-3-piperidino-4'-phenylpropiophenone,2-methyl-3-piperidino-1-(benzo[b]thiophene-3'-yl)-propanone-1,4'-hexyl-2-methyl-3-piperidinopropiophenone,2-methyl-3-piperidino-5',6',7',8'-tetrahydro-2'-propionaphthone,2-methyl-3-(3'-methylpiperidino)-β-propionaphthone,2-methyl-3-(4'-methylpiperazino)-β-propionaphthone,2-methyl-3-(2-methylpiperidino-β-propionaphthone,2-methyl-3-(4-benzylpiperidino)-β-propionaphthone,3',4'-dimethyl-3-piperidinopropiophenone,3-piperidino-β-propionaphthone, 2-ethyl-3-piperidino-β-propionaphthone,1-(5-indanyl)-2-methyl-3-piperidinopropanone,3',4'-diethyl-2-methyl-3-piperidinopropiophenone,2-methyl-3-piperidinopropiophenone, 4'-n-propyl-2-methyl-3-piperidinopropiophenone,2,2',4',6'-tetramethyl-3-piperidinopropiophenone, 2,2',3',4',5',6'-hexamethyl-3-piperidinopropiophenone,6'-methoxy-3-piperidino-2'-propionaphthone,6'-methoxy-2-methyl-3-piperidino-2'-propionaphthone,4'-n-hexyl-3-piperidinopropiophenone,4'-n-heptyl-3-piperidinopropiophenone,4'-n-octyl-3-piperidinopropiophenone,4'-n-decyl-3-piperidinopropiophenone,1'-hydroxy-2-methyl-3-piperidino-2'-propionaphthone,4'-n-heptyl-2-methyl-3-piperidinopropiophenone,2-methyl-4'-n-octyl-3-piperidinopropiophenone,4'-n-decyl-2-methyl-3-piperidinopropiophenone,3'-chloro-4'-methoxy-2-methyl-3-piperidinopropiophenone,3',4'-dichloro-2-methyl-3-piperidinopropiophenone,2,6'-dimethyl-3-piperidino-2'-propionaphthone,6'-hydroxy-2-methyl-3-piperidino-2'-propionaphthone,6'-chloro-2-methyl-3-piperidino-2'-propionaphthone,4'-isopropyl-2-methyl-3-piperidinopropiophenone,4'-n-butyl-2-methyl-3-piperidinopropiophenone,4'-isobutyl-2-methyl-3-piperidinopropiophenone,4'-tert-butyl-2-methyl-3-piperidinopropiophenone,6'-methoxy-2-methyl-3-dimethylamino-2'-propionaphthone,6'-methoxy-2-methyl-3-(4-methylpiperidino)-2'-propionaphthone and4'-methyl-2-phenyl-3-piperidinopropiophenone, and pharmacologicallyallowable salts of these compounds.

The compound according to the present invention can be obtained byreactinga compound expressed by the general formula (II):##STR2##wherein A and R¹ denote the same meanings as above, with aformaldehyde, and a compound of the general formula (III):

    HB                                                         (III)

wherein B denotes the same meaning as above, or its salt.

For the above reaction it is preferable to use solvent which producesazeotropic mixture with water, especially a solvent system whichseparatesfrom water when the azeotropic mixture with water is condensed.Such solvents are, for example, ethanol, benzene, toluene, nitroalkanesor lower esters of lower fatty acid. These are employed singly or asmixed; and the reaction temperature can be controlled to a desired rangeby appropriately combining them.

The formaldehydes to be used for the above reaction include formaldehydeand its linear or cyclic polymers.

The compounds according to the present invention are yielded in the formoffree base or its salt. This salt can be converted in a free base bythe known method in the art. Meanwhile this free base can be turned intoa pharmacologically allowable salt through contact with an inorganic ororganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid,formic acid, lactic acid, tartaric acid, citric acid, etc.

The manufacturing process of the compound according to the presentinvention is explained in detail by working examples.

EXAMPLE 1

A mixture of 125 ml of nitromethane, 35 ml of toluene, 20 ml of ethanol,and 1 ml of concentrated hydrochloric acid was mixed together with 18.6g of 4'-methylpropiophenone, 27.0 g of N-isobutylpiperazinedihydrochloride and 8.5 g of trioxane. The mixture was heated withstirring under reflux for 4 hrs. while distilling off water generatedthrough the reaction. After cooling, the reaction mixture was added withether, and the precipitate was filtered, which was dissolved in water.The solution was adjusted to pH 6 with 5 N sodium hydroxide, washed withether, and furtheradjusted to pH 7 with 5 N sodium hydroxide. Theobtained solution was extracted with ether and the extract was dried,and white crystals generated by introducing dry hydrogen chloride werefiltered and dried. The product was recrystallized from anethanol-acetone mixed solvent, yielding2,4'-dimethyl-3-(4-isobutylpiperazino)propiophenone dihydrochloride.(yield 46.5%), m.p. 215°-220° C.

Elementary analysis (C₁₉ H₃₀ N₂ O.2HCl)

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        Calculated: 60.79  8.59       7.46 18.89                                      Found:      60.54  8.65       7.60 18.80                                      ______________________________________                                    

EXAMPLE 2

283 ml of azeotropic solvent (200 ml of nitromethane, 28 ml of ethanoland 55 ml of toluene), 36.8 g of β-propionaphthone, 36.5 g of piperidinehydrochloride, 13.5 g of paraformaldehyde and 1 ml of concentratedhydrochloric acid were mixed and the mixture was heated under reflux for2hrs. while distilling off water generated during the reaction. Theprecipitate obtained after addition of nitromethane and cooling wasfiltered and dried. Through recrystallization from a mixture ofmethanol: acetone (1:3) and then from ethanol, 33 g of crystallinepowder of 2-methyl-3-piperidino-β-propionaphthone hydrochloride wasobtained. (yield 52.0%), m.p. 196°-197° C.

Elementary analysis (C₁₉ H₂₃ NO.HCl)

    ______________________________________                                                  C %        H %    N %                                               ______________________________________                                        Calculated: 71.80        7.61   4.41                                          Found:      71.66        7.74   4.49                                          ______________________________________                                    

EXAMPLE 3

A mixture of 200 ml of azeotropic solvent (140 ml of nitromethane, 21 mlofethanol, and 39 ml of toluene) and 2 ml of concentrated hydrochloricacid was added with 36.0 g of β-propionaphthone, 24.5 g of dimethylaminehydrochloride and 13.5 g of paraformaldehyde and the mixture was heatedunder reflux for 1.5 hrs. while distilling off water generated throughthereaction. After cooling, the solvent was removed from the reactionmixture by distillation under reduced pressure. The residue wasdissolved in water. The solution was washed with ether, and adjusted tobe alkaline with 5 N sodium hydroxide. The alkaline solution wasextracted with ether and the ether extract was washed with water andthen dried. Next, the crystals yielded by introducing dry hydrogenchloride were filtered and recrystallized from ethanolacetone, yielding24.0 g of white crystals of 2-methyl-3-dimethylamino-β-propionaphthonehydrochloride. (yield 43.2%), m.p. 160°-161° C.

Elementary analysis (C₁₆ H₁₇ NO.HCl)

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        Calculated: 69.18  7.26       5.04 12.76                                      Found:      69.07  7.19       5.08 12.65                                      ______________________________________                                    

EXAMPLE 4

40 g of β-propionaphthone, 12.5 g of paraformaldehyde and 37 g ofmorpholine hydrochloride were dissolved in 300 ml of azeotropic solvent(210 ml of nitromethane, 30 ml of ethanol and 60 ml of benzene) andadded with 1 ml of concentrated hydrochloric acid. The mixture washeated with stirring under reflux for 2 hrs. while distilling off watergenerated during the reaction. The reaction mixture was concentratedunder reduced pressure. The crystals precipitated were washed with etherand filtered. The crystals were suspended in ethanol, heated underreflux, and filtered after cooling to yield crude crystals, which wererecrystallized from methanol, yielding 55.3 g of milky white crystallinepowder of 2-methyl-3-morpholino-β-propionaphthone hydrochloride. (yield79.6%),m.p. 182.5°-182.8° C.

Elementary analysis (C₁₈ H₂₁ NO₂.HCl)

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        Calculated: 67.60  6.93       4.38 11.08                                      Found:      67.55  6.88       4.36 10.94                                      ______________________________________                                    

EXAMPLE 5

72.0 g of 3',4'-dimethylpropiophenone, 59.4 g of piperidinehydrochloride and 20.0 g of paraformaldehyde, 300 ml of ethyl acetateand 1 ml of concentrated hydrochloric acid were heated with stirringunder reflux for 2.5 hours, while distilling off water generated throughthe reaction. After cooling, crystals precipitated were filtered andrecrystallized froma mixture of alcohol-acetone, yielding white crystalsof the object product. Each filtrate was collected, concentrated underreduced pressure to dryness, and dissolved in water. The solution waswashed with ether, then adjusted to be alkaline with 5 N sodiumhydroxide and extracted with ether. The extract was washed and thenether was removed after addition ofconcentrated hydrochloric acid, andthe residue was recrystallized from a mixture of alcohol-acetone,yielding white crystals of 2,3',4'-trimethyl-3-piperidinopropiophenonehydrochloride (total yield 61.3%), m.p. 184°-185° C.

Elementary analysis (C₁₇ H₂₅ NO.HCl)

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        Calculated: 69.02  8.86       4.73 11.98                                      Found:      68.81  8.60       4.88 11.90                                      ______________________________________                                    

EXAMPLE 6

36.8 g of β-propionaphthone, 13.5 g of paraformaldehyde and 21.5 g ofpyrrolidine were dissolved in 285 ml of azeotropic solvent (200 ml ofnitromethane, 30 ml of ethanol and 55 ml of toluene) and added with 30ml of concentrated hydrochloric acid. The mixture was heated underreflux for2 hrs. while distilling off water generated through thereaction. The reaction mixture was concentrated under reduced pressureand the crystals precipitated were washed with acetone and filtered off.The product was dissolved in water, washed with ether, adjusted to bealkaline with 5 N sodium hydroxide, and extracted with ether. Theextract was washed with water and dried over anhydrous sodium sulfate,and the crystals yielded byintroducing dry hydrogen chloride werefiltered. Through recrystallization from alcohol-acetone and water, 10.5g of crystalline powder of 2-methyl-3-pyrrolidino-β-propionaphthonehydrochloride was obtained (yield 17.3%), m.p. 189°-190° C.

Elementary analysis (C₁₈ H₂₁ NO.HCl)

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        Calculated: 71.16  7.30       4.61 11.67                                      Found:      71.05  7.34       4.61 11.58                                      ______________________________________                                    

EXAMPLE 7

A mixture of 210 ml of nitromethane, 32 ml of ethanol, 58 ml of tolueneand2 ml of concentrated hydrochloric acid was added with 38.8 g of3',4'-dimethoxypropiophenone, 26.8 g of piperidine hydrochloride and 9.0gof paraformaldehyde. The mixture was heated under reflux for 1.5 hrs.whiledistilling off water generated through the reaction. The reactionmixture was concentrated under reduced pressure. The crystalsprecipitated were washed with acetone and filtered. Recrystallization ofthis product from amixture of alcoholacetone gave white crystallinepowder of the object compound. The mother liquor of recrystallizationwas concentrated under reduced pressure to dryness and the residue wasdissolved in water. The solution was washed with ether and adjusted tobe alkaline with 5 N sodiumhydroxide, extracted with ether and the etherextract was washed with waterand then dried over anhydrous sodiumsulfate. The crystals obtained by introducing dry hydrogen chloride werefiltered and through recrystallization from a mixture ofethanol-acetone, white crystalline powder of3',4'-dimethoxy-2-methyl-3-piperidinopropiophenone hydrochloridewasobtained. (total yield 32.0%), m.p. 171°-172° C.

Elementary analysis (C₁₇ H₂₅ NO₃.HCl)

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        Calculated: 62.28  7.99       4.27 10.81                                      Found:      62.40  7.97       4.19 10.78                                      ______________________________________                                    

EXAMPLE 8

A mixture of 125 ml of nitromethane, 20 ml of ethanol, 35 ml of tolueneand2 ml of concentrated hydrochloric acid was added with 22.6 g ofp-methoxyphenyl benzyl ketone, 18.2 g of piperidine hydrochloride and6.9 g of paraformaldehyde. The mixture was heated under reflux for 1.5hrs. while distilling off water generated through the reaction. Aftercooling, the solvent was removed from the reaction mixture under reducedpressure. The residue was dissolved in water, and the solution wasextracted with ether, then with benzene, and the extract was dried overanhydrous sodium sulfate. Recrystallization of the product frommethanol-acetone after removal of the solvent gave 14.5 g of whitecrystals of 4'-methoxy-2-phenyl-3-piperidinopropiophenone hydrochloride.(yield 40.3%), m.p. 148°-149° C.

Elementary analysis (C₂₁ H₂₅ NO₂.HCl)

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        Calculated: 70.08  7.28       3.89 9.85                                       Found:      69.83  7.44       3.87 9.71                                       ______________________________________                                    

EXAMPLE 9

A mixture of 140 ml of nitromethane, 40 ml of toluene, 20 ml of ethanoland2 ml of concentrated hydrochloric acid was mixed with 37.7 g of6-propionyltetralin, 26.8 g of piperidine hydrochloride and 9.0 g offormaldehyde (used in the form of 40% aqueous formaldehyde). The mixturewas heated under reflux for 1 hr. while distilling off water generatedduring the reaction. After cooling, the crystals precipitated werefiltered and recrestallized from a mixture of alcohol-acetone to yieldwhite crystalline powder of the object compound. The filtrate ofrecrystallization was concentrated under reduced pressure to dryness,and the residue was dissolved in water. The solution was washed withether, adjusted to be alkaline with 1 N sodium hydroxide, and extractedwith ether. The extract was washed with water, and dried over anhydroussodium sulfate. Crystals precipitated by introducing dry hydrogenchloride was filtered. Recrystallization of the product fromalcohol-acetone gave whitecrystalline powder of2-methyl-3-piperidino-5',6',7',8'-tetrahydro-2'-propionaphthonehydrochloride. (total yield 54.1%), m.p. 175.5°-176.5° C.

Elementary analysis (C₁₉ H₂₇ NO·HCl)

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        Calculated: 70.90  8.77       4.35 11.01                                      Found:      70.74  8.92       4.39 10.95                                      ______________________________________                                    

EXAMPLE 10

A mixture of 18.4 g of β-propionaphthone, 14.9 g of3-methylpiperidinehydrochloride, 4.5 g of paraformaldehyde, 1 ml ofhydrochloric acid and 250ml of ethyl acetate was heated for 2.5 hoursunder reflux while distilling off water generated during the reaction.After cooling, the crystals precipitated were filtered, andrecrystallized from a mixture of alcohol-acetone, yielding 15.2 g ofwhite crystalline powder of2-methyl-3-(3-methylpiperidino)-β-propionaphthone hydrochloride. (yield45.8%), m.p. 175.5°-177° C.

Elementary analysis (C₂₀ H₂₅ NO.HCl)

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        Calculated: 72.38  7.90       4.22 10.68                                      Found:      71.80  7.92       4.10 10.66                                      ______________________________________                                    

Examples 11-58

According to the substantially same process as described in Examples1-10, the products as listed in Table 2 were obtained from the startingmaterials listed in Table 1.

                                      TABLE 1                                     __________________________________________________________________________    Example No.                                                                          Starting compounds (II)                                                                         Starting compounds (III)                             __________________________________________________________________________    11     4'-methylpropiophenone                                                                          diethylamine hydrochloride                           12       "               morpholine hydrochloride                             13       "               pyrrolidine                                          14       "               1-methylpiperazine dihydro-                                                   chloride                                             15       "               1-ethylpiperazine dihydro-                                                    chloride                                             16       "               N-benzylpiperazine dihydro-                                                   chloride                                             17     4'-hydroxypropiophenone                                                                         piperidine hydrochloride                             18     4'-hydroxy-3'-methoxy-                                                                          "                                                           propiophenone                                                          19     α-propionaphthone                                                                         "                                                    20     4'-phenylpropiophenone                                                                          "                                                    21     1-(benzo[b]thiophene-                                                                           "                                                           3'-yl)propanone-1                                                      22     4'-hexylpropiophenone                                                                           "                                                    23     β-propionaphthone                                                                          4-methylpiperidine hydro-                                                     chloride                                             24     4'-methylpropiophenone                                                                          dimethylamine hydrochloride                          25     4'-methoxypropiophenone                                                                         piperidine hydrochloride                             26     4'-ethoxypropiophenone                                                                          "                                                    27     p-tolyl benzyl ketone                                                                           "                                                    28     β-propionaphthone                                                                          2-methylpiperidine hydro-                                                     chloride                                             29       "               4-benzylpiperidine hydro-                                                     chloride                                             30     3',4'-dimethylaceto-                                                                            piperidine hydrochloride                                    phenone                                                                31     β-acetonaphthone                                                                           "                                                    32     β-butyronaphthone                                                                          "                                                    33     5-propionylindane "                                                    34     3',4'-diethylpropio-                                                                            "                                                           phenone                                                                35     propiophenone     "                                                    36     4'-n-propyl-      "                                                           propiophenone                                                          37     2',4',6'-trimethyl-                                                                             "                                                           propiophenone                                                          38     2',3',4',5',6'-   "                                                           pentamethyl-                                                                  propiophenone                                                          39     6'-methoxy-2'-acetonaphthone                                                                    "                                                    40     6'-methoxy-2'-propionaphthone                                                                   "                                                    41     4'-n-hexylacetophenone                                                                          "                                                    42     4'-n-heptylacetophenone                                                                         "                                                    43     4'-n-octylacetophenone                                                                          "                                                    44     4'-n-decylacetophenone                                                                          "                                                    45     1'-hydroxy-2'-propionaphthone                                                                   "                                                    46     4'-n-heptylpropiophenone                                                                        "                                                    47     4'-n-octylpropiophenone                                                                         "                                                    48     4'-n-decylpropiophenone                                                                         "                                                    49     3'-chloro-4'-methoxypropiophenone                                                               "                                                    50     3',4'-dichloropropiophenone                                                                     "                                                    51     6'-methyl-2'-propionaphthone                                                                    "                                                    52     6'-chloro-2'-propionaphthone                                                                    "                                                    53     4'-isopropylpropiophenone                                                                       "                                                    54     4'-n-butylpropiophenone                                                                         "                                                    55     4'-isobutylpropiophenone                                                                        "                                                    56     4'-tert-butylpropiophenone                                                                      "                                                    57     6'-methoxy-2'-propionaphthone                                                                   dimethylamine hydro-                                                          chloride                                             58       "               4-methylpiperidine                                                            hydrochloride                                        __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________                             Melting Point (°C.)                                                              Elementary analysis**                      Example                  (Solvent for                                                                            (%)                                        No.    Product (I)       recrystallization)*                                                                     C  H  N  Cl                                __________________________________________________________________________    11   2,4'-dimethyl-3-diethylamino-                                                                     88.0-89.0 62.60                                                                            9.11                                                                             4.87                                                                             13.14                                  propiophenone hydrochloride   62.88                                                                            9.40                                                                             5.16                                                                             13.02                             12   2,4'-dimethyl-3-morpholino-                                                                       155.0-155.5                                                                             63.48                                                                            7.82                                                                             4.94                                                                             12.49                                  propiophenone hydrochloride                                                                       (MEK--EtOH)                                                                             63.22                                                                            7.92                                                                             5.02                                                                             12.50                             13   2,4'-dimethyl-3-pyrrolidino-                                                                      156.0-157.0                                                                             67.28                                                                            8.28                                                                             5.23                                                                             13.24                                  propiophenone hydrochloride                                                                       (acetone) 67.45                                                                            8.50                                                                             5.42                                                                             13.08                             14   2,4'-dimethyl-3-(4-methylpiperazino)-                                                             190.0-193.0                                                                             56.69                                                                            7.83                                                                             8.26                                                                             20.92                                  propiophenone dihydrochloride                                                                     (MtOH-acetone)                                                                          56.66                                                                            7.92                                                                             8.29                                                                             21.84                             15   2,4'-dimethyl-3-(4-ethylpiperazino)-                                                              178.0-179.0                                                                             58.79                                                                            8.13                                                                             8.06                                                                             20.41                                  propiophenone dihydrochloride                                                                     (EtOH-acetone)                                                                          58.77                                                                            8.16                                                                             7.94                                                                             20.23                             16   2,4'-dimethyl-3-(4-benzylpiperazino)-                                                             217.0-245 (Dec.)                                                                        64.54                                                                            7.39                                                                             6.84                                                                             17.32                                  propiophenone dihydrochloride                                                                     (MtOH)    64.34                                                                            7.47                                                                             6.91                                                                             17.53                             17   4'-hydroxy-2-methyl-3-piperidino-                                                                 197.0-198.0                                                                             63.48                                                                            7.81                                                                             4.94                                                                             12.49                                  propiophenone hydrochloride                                                                       (EtOH-acetone)                                                                          63.25                                                                            7.95                                                                             5.06                                                                             12.37                             18   4'-hydroxy-3'-methoxy-2-methyl-3-                                                                 156.0-157.0                                                                             61.24                                                                            7.71                                                                             4.46                                                                             11.30                                  piperidinopropiophenone hydrochloride                                                             (EtOH-acetone)                                                                          61.34                                                                            7.73                                                                             4.38                                                                             11.25                             19   2-methyl-3-piperidino-α-propionaphthone                                                     165.0-166.0                                                                             71.80                                                                            7.61                                                                             4.41                                                                             11.15                                  hydrochloride       (H.sub.2 O-acetone)                                                                     71.67                                                                            7.81                                                                             4.38                                                                             11.04                             20   2-methyl-3-piperidino-4'-phenyl-                                                                  174.5-175.5                                                                             73.35                                                                            7.62                                                                             4.07                                                                             10.31                                  propiophenone hydrochloride                                                                       (EtOH-acetone)                                                                          73.61                                                                            7.57                                                                             4.19                                                                             10.26                             21   2-methyl-3-piperidino-1-(benzo[b]thio-                                                            164.0-165.0                                                                             63.04                                                                            6.85                                                                             4.32                                                                             10.95                                  phene-3-yl)propanone-1 hydrochloride                                                              (methyl isobutyl                                                                        62.77                                                                            6.91                                                                             4.42                                                                             10.83                                                      ketone)                                              22   4'-hexyl-2-methyl-3-piperidinopropio-                                                             157.5-158.5                                                                             71.66                                                                            9.74                                                                             3.95                                                                             10.07                                  phenone hydrochloride                                                                             (EtOH-acetone)                                                                          71.57                                                                            9.68                                                                             3.81                                                                             10.01                             23   2-methyl-3-(4-methylpiperidino)-β-                                                           187-188   72.38                                                                            7.90                                                                             4.22                                                                             10.68                                  propionaphthone hydrochloride                                                                     (alcohol-acetone)                                                                       72.20                                                                            7.78                                                                             4.18                                                                             10.71                             24   2,4'-dimethyl-3-dimethylamino-                                                                    145.0-146.0                                                                             64.70                                                                            8.34                                                                             5.79                                                                             14.66                                  propiophenone hydrochloride                                                                       (MEK--EtOH)                                                                             63.56                                                                            8.31                                                                             5.82                                                                             14.55                             25   4'-methoxy-2-methyl-3-piperidino-                                                                 168.0-168.5                                                                             64.53                                                                            8.12                                                                             4.72                                                                             11.90                                  propiophenone hydrochloride                                                                       (MEK--EtOH)                                                                             64.25                                                                            8.15                                                                             4.66                                                                             11.91                             26   4'-ethoxy-2-methyl-3-piperidinopropio-                                                            164.0-165.0                                                                             65.48                                                                            8.48                                                                             4.49                                                                             11.34                                  phenone hydrochloride                                                                             (isopropanol)                                                                           65.59                                                                            8.61                                                                             4.52                                                                             11.44                             27   4'-methyl-2-phenyl-3-piperidino-                                                                  162.0-162.5                                                                             73.35                                                                            7.62                                                                             4.07                                                                             10.31                                  propiophenone hydrochloride                                                                       (MtOH-acetone)                                                                          73.20                                                                            7.71                                                                             4.02                                                                             10.27                             28   2-methyl-3-(2-methylpiperidino)-                                                                  135.5-136.5                                                                             72.38                                                                            7.90                                                                             4.22                                                                             10.68                                  β-propionaphthone hydrochloride                                                              (MEK-ether)                                                                             72.29                                                                            7.84                                                                             4.20                                                                             10.66                             29   2-methyl-3-(4-benzylpiperidino)-                                                                  171-172   76.54                                                                            7.41                                                                             3.43                                                                             8.69                                   β-propionaphthone hydrochloride                                                              (alcohol-acetone-                                                                       76.86                                                                            7.86                                                                             3.62                                                                             8.66                                                       ether)                                               30   3',4'-dimethyl-3-piperidino-                                                                      182-183   68.19                                                                            8.58                                                                             4.97                                                                             12.58                                  propiophenone hydrochloride                                                                       (alcohol-ether)                                                                         68.34                                                                            8.67                                                                             5.07                                                                             12.54                             31   3-piperidino-β-propionaphthone                                                               191-192   71.16                                                                            7.30                                                                             4.61                                                                             11.67                                  hydrochloride       (MtOH-ether)                                                                            70.68                                                                            7.86                                                                             4.62                                                                             11.56                             32   2-ethyl-3-piperidino-β-                                                                      176-177   72.38                                                                            7.90                                                                             4.22                                                                             10.68                                  propionaphthone hydrochloride                                                                     (alcohol-acetone-                                                                       72.30                                                                            7.92                                                                             4.18                                                                             10.57                                                      ether)                                               33   1-(5-indanyl)-2-methyl-3-                                                                         187-188   70.23                                                                            8.51                                                                             4.55                                                                             11.52                                  piperidinopropanone hydrochloride                                                                 (alcohol-acetone)                                                                       70.37                                                                            8.71                                                                             4.54                                                                             11.59                             34   3',4'-diethyl-2-methyl-3-piperidino-                                                              157-158   70.46                                                                            9.34                                                                             4.32                                                                             10.95                                  propiophenone hydrochloride                                                                       (alcohol-acetone-                                                                       70.60                                                                            9.18                                                                             4.30                                                                             10.38                                                      ether)                                               35   2-methyl-3-piperidinopropiophenone                                                                178-179   67.28                                                                            8.28                                                                             5.23                                                                             13.24                                  hydrochloride       (alcohol-acetone)                                                                       67.46                                                                            8.20                                                                             5.18                                                                             13.19                             36   4'-n-propyl-2-methyl-3-piperidino-                                                                169-170   69.77                                                                            9.11                                                                             4.52                                                                             11.44                                  propiophenone hydrochloride                                                                       (alcohol-acetone-                                                                       69.99                                                                            9.04                                                                             4.55                                                                             11.44                                                      ether)                                               37   2,2',4',6'-tetramethyl-3-                                                                         133-135   69.77                                                                            9.11                                                                             4.52                                                                             11.44                                  piperidinopropiophenone hydrochloride                                                             (alcohol-acetone-                                                                       69.83                                                                            9.15                                                                             4.57                                                                             11.35                                                      ether)                                               38   2,2',3',4',5',6'-hexamethyl-3-piperi-                                                             220-223   71.09                                                                            9.54                                                                             4.14                                                                             10.49                                  dinopropiophenone hydrochloride                                                                   (alcohol-ether)                                                                         70.91                                                                            9.57                                                                             4.13                                                                             10.48                             39   6'-methoxy-3-piperidino-                                                                          190.5-192.0                                                                             68.35                                                                            7.25                                                                             4.20                                                                             10.62                                  2'-propionaphthone  (MtOH)    68.19                                                                            7.22                                                                             4.31                                                                             10.58                                  hydrochloride                                                            40   6'-methoxy-2-methyl-3-                                                                            185.5-186.0                                                                             69.05                                                                            7.53                                                                             4.03                                                                             10.19                                  piperidino-2'-propio-                                                                             (MtOH)    69.00                                                                            7.46                                                                             4.20                                                                             10.02                                  naphthone hydrochloride                                                  41   4'-n-hexyl-3-piperidino-                                                                          159       71.08                                                                            9.54                                                                             4.14                                                                             10.49                                  propiophenone hydro-                                                                              (acetone) 71.05                                                                            9.55                                                                             4.08                                                                             10.55                                  chloride                                                                 42   4'-n-heptyl-3-piperidino-                                                                         154       71.66                                                                            9.74                                                                             3.98                                                                             10.07                                  propiophenone hydro-                                                                              (acetone) 71.61                                                                            9.67                                                                             4.05                                                                             10.10                                  chloride                                                                 43   4'-n-octyl-3-piperidino-                                                                          157       72.20                                                                            9.92                                                                             3.83                                                                             9.69                                   propiophenone hydro-                                                                              (acetone) 72.11                                                                            9.86                                                                             3.93                                                                             9.85                                   chloride                                                                 44   4'-n-decyl-3-piperidino-                                                                          151       73.16                                                                            10.23                                                                            3.55                                                                             9.00                                   propiophenone hydro-                                                                              (acetone) 73.23                                                                            10.20                                                                            3.59                                                                             8.98                                   chloride                                                                 45   1'-hydroxy-2-methyl-3-                                                                            96-97.5   68.35                                                                            7.25                                                                             4.20                                                                             10.62                                  piperidino-2'-propio-                                                                             (MtOH)    68.09                                                                            7.16                                                                             4.35                                                                             10.58                                  naphthone hydrochloride                                                  46   4'-n-heptyl-2-methyl-3-                                                                           152.5-153.5                                                                             72.20                                                                            9.92                                                                             3.83                                                                             9.69                                   piperidinopropiophenone                                                                           (acetone) 72.18                                                                            9.95                                                                             4.00                                                                             9.74                                   hydrochloride                                                            47   2-methyl-4'-n-octyl-3-                                                                            148-149.5 72.69                                                                            10.08                                                                            3.69                                                                             9.33                                   piperidinopropiophenone                                                                           (acetone) 72.73                                                                            10.32                                                                            3.60                                                                             9.32                                   hydrochloride                                                            48   4'-n-decyl-2-methyl-3-                                                                            143.5-144.5                                                                             73.58                                                                            10.37                                                                            3.43                                                                             8.69                                   piperidinopropiophenone                                                                           (acetone) 73.79                                                                            10.25                                                                            3.40                                                                             8.63                                   hydrochloride                                                            49   3'-chloro-4'-methoxy-2-                                                                           161.5-162.5                                                                             57.84                                                                            6.98                                                                             4.22                                                                             21.34                                  methyl-3-piperidino-                                                                              (EtOH-acetone)                                                                          57.90                                                                            7.01                                                                             4.08                                                                             21.38                                  propiophenone hydro-                                                          chloride                                                                 50   3',4'-dichloro-2-methyl-                                                                          176.0     53.51                                                                            5.99                                                                             4.16                                                                             31.59                                  3-piperidinopropiophenone                                                                         (acetone) 53.67                                                                            5.98                                                                             4.11                                                                             31.38                                  hydrochloride                                                            51   2,6'-dimethyl-3-piperidino-                                                                       194.0-194.5 (Dec.)                                                                      72.38                                                                            7.90                                                                             4.22                                                                             10.68                                  2'-propionaphthone hydro-                                                                         (EtOH)    72.51                                                                            7.83                                                                             4.21                                                                             10.69                                  chloride                                                                 52   6' -chloro-2-methyl-3-                                                                            201-202 (Dec.)                                                                          64.78                                                                            6.58                                                                             3.98                                                                             20.13                                  piperidino-2'-propio-                                                                             (MtOH)    64.87                                                                            6.69                                                                             4.09                                                                             20.09                                  naphthone hydrochloride                                                  53   4'-isopropyl-2-methyl-3-                                                                          181-182   69.77                                                                            9.11                                                                             4.52                                                                             11.44                                  piperidinopropiophenone                                                                           (acetone) 69.83                                                                            9.21                                                                             4.61                                                                             11.36                                  hydrochloride                                                            54   4'-n-butyl-2-methyl-3-                                                                            161-162   70.45                                                                            9.34                                                                             4.32                                                                             10.95                                  piperidinopropiophenone                                                                           (acetone) 70.57                                                                            9.25                                                                             4.33                                                                             10.98                                  hydrochloride                                                            55   4'-isobutyl-2-methyl-                                                                             172-173   70.45                                                                            9.34                                                                             4.32                                                                             10.95                                  3-piperidinopropiophenone                                                                         (acetone) 70.71                                                                            9.31                                                                             4.45                                                                             10.96                                  hydrochloride                                                            56   4'-tert-butyl-2-methyl-                                                                           168-169   70.45                                                                            9.34                                                                             4.32                                                                             10.95                                  3-piperidinopropiophenone                                                                         (acetone) 70.56                                                                            9.36                                                                             4.25                                                                             10.92                                  hydrochloride                                                            57   6'-methoxy-2-methyl-3-                                                                            177.5-178.5                                                                             66.33                                                                            7.20                                                                             4.55                                                                             11.52                                  dimethylamino-2'-   (EtOH-acetone)                                                                          66.45                                                                            7.12                                                                             4.61                                                                             11.48                                  propionaphthone hydro-                                                        chloride                                                                 58   6'-methoxy-2-methyl-3-                                                                            191.5-193.5 (Dec.)                                                                      69.69                                                                            7.80                                                                             3.87                                                                             9.80                                   (4-methylpiperidino)-2'-                                                                          (EtOH-acetone)                                                                          69.80                                                                            7.65                                                                             3.83                                                                             9.70                                   propionaphthone hydro-                                                        chloride                                                                 __________________________________________________________________________    *MEK: methyl ethyl ketone, MtOH: methanol, EtOH: ethanol                      **upper figure: Calculated value                                              lower figure: Found value                                                 

The present invention intends also to produce the compounds havinghydroxy group other than those in the Table by dealkylating,dearalkylating or hydrolyzing the compounds having alkoxy group,aralkyloxy group or acyloxygroup at aryl moiety respectively, by meansof the process publicly known in itself. Namely, this process isespecially recommended in such a case that it is hard to produce thecompounds according to the present invention directly from hydroxysubstituted arylketones.

The following is a concrete example of this process.

EXAMPLE 59

A mixture of 3.3 g of6'-benzyloxy-2-methyl-3-piperidino-2'-propionaphthonehydrochloride, 5 mlof concentrated hydrochloric acid and 40 ml of acetic acid was agitatedunder heating at 90° C. for 6 hours. Aqueous solution of sodiumbicarbonate was added thereto, and the mixture was extracted withether-ethyl acetate (2:1). After washing with water, 1% hydrochloricacid was added to move the object product to aqueous phase. It waswashed with ether-ethyl acetate and made to be alkaline by aqueoussolution of sodium bicarbonate, and then extracted by ether. Afterwashingwith water and drying, purification by silica gel columnchromatography andactive carbon treatment were conducted. Crystalsobtained by concentrating under reduced pressure were recrystallizedfrom ethanol-ether, thus producing 1.0 g of6'-hydroxy-2-methyl-3-piperidino-2'-propionaphthone hydrochloride oflight-brown crystals.

m.p. 188°-189° C.

Elementary analysis (C₁₉ H₂₃ NO₂.HCl)

    ______________________________________                                                  C %  H %        N %    Cl %                                         ______________________________________                                        Calculated: 68.35  7.25       4.20 10.62                                      Found:      68.50  7.33       4.18 10.56                                      ______________________________________                                    

The following results of toxic and pharmacological tests prove theactivity, particularly the antiallergic activity, of the compoundsaccording to the present invention.

Thus the present invention relates to pharmaceutical compositionscontaining as the active ingredient the compounds expressed by theformula(I) or the pharmacologically allowable salts thereof.

ACUTE TOXICITY

Acute toxicity tests were carried out by intraperitoneal or peroraladministration of the compound according to the present invention togroups of 10 ICR-strain male mice (weighing 20 g on the average), andeachLD₅₀ value was determined by Litchfield-Wilcoxon Method.

As the result it was found that the compounds according to the presentinvention showed the following values of LD₅₀ : for instance,2-methyl-3-piperidino-β-propionaphthone hydrochloride, 120 mg/kgwhenadministered intraperitoneally, 370 mg/kg when administeredperorally; 2-methyl-3-morpholino-β-propionaphthone hydrochloride, 190mg/kg whenadministered intraperitoneally, 540 mg/kg when administeredperorally; 2,3',4'-trimethyl-3-piperidinopropiophenone hydrochloride,117 mg/kg when administered intraperitoneally, 325 mg/kg whenadministered perorally; theother compounds exhibiting about the samevalues of LD₅₀.

PHARMACOLOGICAL TESTS (1) Anti-SRS-A effect

The anti-SRS-A effect of the compounds according to the presentinvention on guinea pig's ileum was measured by Magnus method.

Isolated ileum of the guinea pig was suspended in a Magnus tube whichwas kept at a temperature of 31°±1° C., and after eliminatingthe effectof histamine by pretreatment with mepyramine, test compound wasadministered at a dosage of 10⁻⁸ -10⁻⁴ g/ml. One minute thereafter, theileum contraction inhibiting rate (%) was measured with use of 1 ml of80% ethanol solution of SRS-A (150 mg/ml). Representative results aresummarized in Table 3.

                  TABLE 3                                                         ______________________________________                                        Example Concentration of test compound (g/ml)                                 No.     10.sup.-6   10.sup.-5   10.sup.-4                                     ______________________________________                                        1       0 ± 0     6.7 ± 3.33                                                                            64.7 ± 7.51                                2       10.0 ± 8.08                                                                            53.7 ± 8.68                                                                            76.0 ± 7.23                                3       1.3 ± 0.88                                                                             47.0 ± 9.50                                                                            91.3 ± 3.84                                4       13.0 ± 12.50                                                                            36.3 ± 14.19                                                                          96.7 ± 3.33                                5       12.3 ± 8.25                                                                            67.7 ± 8.11                                                                            100.0 ± 0                                  6       0.3 ± 0.33                                                                             63.0 ± 6.66                                                                            100.0 ± 0                                  7       1.0 ± 1.00                                                                              8.3 ± 2.85                                                                            85.7 ± 0.67                                11      3.0 ± 3.00                                                                              0.3 ± 0.33                                                                             68.0 ± 13.05                              12      8.3 ± 6.89                                                                             20.7 ± 5.61                                                                             69.7 ± 12.13                              13      1.3 ± 1.33                                                                              2.7 ± 2.67                                                                            80.7 ± 6.98                                14      10.3 ± 7.98                                                                            10.3 ± 7.88                                                                            58.0 ± 4.36                                15      0.3 ± 0.33                                                                             20.7 ± 6.12                                                                            69.7 ±  3.71                               24      4.3 ± 2.40                                                                              7.7 ± 3.67                                                                            57.3 ± 5.17                                25      6.7 ± 6.67                                                                              15.0 ± 14.50                                                                          80.3 ± 7.22                                26      6.7 ± 5.24                                                                             12.3 ± 6.69                                                                            86.7 ± 3.84                                ______________________________________                                    

(2) Inhibitory effect on histamine release

The inhibitory effect on histamine release of the compounds according tothe present invention was investigated as follows.

Peritoneal cavity cells of 6-8 weeks old Wistar-strain male rats weresensitized by incubation at 37° C. for 2 hours in a rat anti-ovalbuminserum (prepared according to the method of Goose et al. [J.Goose,Immunology 16, 749, 1969]). These cells were suspended in a phosphoricacid buffer solution (containing 0.1% of gelatin) and each 0.5 mlportion of this suspension was taken in a polyethylene tube. 1 ml eachof solutions of various concentrations of test compound and 0.5 ml of200 μg/ml of ovalbumin solution were added therein. They were incubatedfor20 minutes at 37° C. to measure the histamine release rate. Theamount of histamine was measured by a modified Shore method usingfluorescence.

As comparisons, 2,4'-dimethyl-3-piperidinopropiophenone and disodiumchromoglicate (DSCG) were employed. Representative results aresummarized in Tables 4-7, and FIGS. 1 and 2.

                  TABLE 4                                                         ______________________________________                                        Test    Fluorescence intensity (%)                                                                      Re-    Net** Inhibi-                                Compound                  Total lease                                                                              release                                                                             tory                               (Example                                                                              Released Residual hista-                                                                              rate rate  effect                             No.)    histamine                                                                              histamine                                                                              mine  (%)  (%)   (%)                                ______________________________________                                        Control 220      252      472   46.6 32.7  --                                 2,4'-di-                                                                              246      238      484   50.8 36.9  0                                  methyl-                                                                       3-pipe-                                                                       ridino-                                                                       propio-                                                                       phenone*                                                                      (2)*    184      292      476   38.6 24.7  24.5                               (4)*    212      268      480   44.2 30.3   7.4                               (5)*    210      280      490   42.9 29.0  11.3                               DSCG*   182      312      494   36.8 22.9  30.0                               ______________________________________                                        *Concentration of test compound: 0.01 mM                                      **Net release rate is calculated by deducting histamine release rate of        sensitized peritoneal cavity cells which is not caused by antigenantibody     reaction from the above release rate.                                    

                  TABLE 5                                                         ______________________________________                                        Test comound                                                                            Concentration of                                                                             Inhibitory effect on                                 (Example No.)                                                                           Test compound (mM)                                                                           histamine release (%)*                               ______________________________________                                        (10)      0.05           18.0 ± 5.4                                        (22)      "              82.0 ± 1.7                                        (23)      "              21.4 ± 2.4                                        (28)      "              18.5 ± 6.5                                        (29)      "              61.0 ± 3.6                                        (30)      "              19.4 ± 7.8                                        (31)      "              53.4 ± 9.1                                        (32)      "              27.2 ± 8.1                                        (33)      "              14.4 ± 2.6                                        (34)      "              29.1 ± 7.5                                        (36)      "              23.6 ± 7.7                                        DSCG      "              29.0 ± 6.1                                        ______________________________________                                        *Average value ± S.E. of 3 or 4 times experiments.                     

                  TABLE 6                                                         ______________________________________                                        Test compound                                                                            Concentration of                                                                             Inhibitory effect on                                (Example No.)                                                                            Test compound (mM)                                                                           histamine release (%)                               ______________________________________                                         2         0.1            60                                                   6         "              48                                                   9         "              33.7                                                10         "              49.9                                                22         "              87.2                                                23         "              65.8                                                28         "              40.7                                                29         "              98.7                                                30         "              50.3                                                31         "              89.6                                                32         "              42.0                                                39         "              85                                                  40         "              84                                                  49         "              38                                                  50         "              73                                                  51         "              37                                                  DSCG       "              70                                                  ______________________________________                                    

                  TABLE 7                                                         ______________________________________                                        Test compound                                                                            Concentration of                                                                             Inhibitory effect on                                (Example No.)                                                                            Test compound (mM)                                                                           histamine release (%)                               ______________________________________                                        16         0.2            72.4                                                18         "              83.7                                                19         "              100                                                 27         "              78.5                                                ______________________________________                                    

As seen from the above results, the compounds according to the presentinvention exhibit prominent anti-SRS-A effect and inhibitory effect onhistamine release, and their effects depend on the dose.

(3) Experimental atopic asthma

Anti-benzylpenicilloyl bovine γ-globulin serum (anti-(BPO)₆₃ -BGG serum)of 2048 titer in 7-day homologous PCA which had been obtained by themethod of Levine et al. [Levine, B. B. et al., J. Immunol., 106,29(1971)] was injected at a dosage of 0.25 ml/guinea pig into the heartsof groups of Hartley-strain male guinea pig (a group consisting offour), each weighing 250-300 g, to make them passively sensitive.Forty-eight hours thereafter, the tracheal muscle is cut open underurethane anesthesia and is connected with transducer (MFP-IT and MP-24Tof Nihon Kohden Kogyo Co., Ltd.), and the velocity and volume ofbreathing were measured simultaneously by a multi-purposemonitor-recorder (RM-150 of Nihon Kohden Kogyo Co., Ltd.). The rate ofbreathing and the ratio of expiration time to inspiration time werecalculated from the velocity of breathing. As an antigen to induce thereaction 200 μg/kg of benzylpenicilloyl bovine serum albumin [(BPO)₂₃-BSA] obtained by themethod of Levine et al. [Levine et al.; J. Clin.Invest., 47, 556 (1968)] was injected through a cannula into the jugularvein.

Compounds according to the present invention and2,4'-dimethyl-3-piperidinopropiophenone were perorally administered at adosage of 50 mg/kg, one hour in advance of reaction induction, theresultsbeing summarized in Table 8.

                                      TABLE 8                                     __________________________________________________________________________                             2,4'-dimethyl-3-piperidino-                          Meas-                                                                             Control              propiophenone                                        ured                                                                              Rate of                                                                              Volume of                                                                            Expiration                                                                           Rate of                                                                              Volume of                                                                            Expiration                             time                                                                              breathing                                                                            breathing                                                                            /inspira-                                                                            breathing                                                                            breathing                                                                            /inspira-                              (min.)                                                                            (%)    (%)    tion (%)                                                                             (%)    (%)    tion (%)                               __________________________________________________________________________    Before                                                                        test                                                                              100.0 ± 0.00                                                                      100.0 ± 0.00                                                                      100.0 ± 0.00                                                                      100.0 ± 0.00                                                                      100.0 ± 0.00                                                                      100.0 ± 0.00                        1   141.7 ± 16.21                                                                     119.8 ± 8.45                                                                       73.8 ± 5.53                                                                      120.6 ± 4.98                                                                      123.4 ± 6.52                                                                      90.2 ± 4.02                         3   90.0 ± 5.58                                                                       75.5 ± 5.86                                                                       120.1 ± 9.46                                                                      98.5 ± 6.55                                                                       92.6 ± 8.29                                                                       93.9 ± 5.09                         6   75.5 ± 2.41                                                                       76.2 ± 6.49                                                                       117.9 ± 7.37                                                                      89.5 ± 3.36                                                                       96.7 ± 3.97                                                                       94.3 ± 5.34                         18  78.9 ± 1.56                                                                       79.7 ± 6.73                                                                       124.8 ± 6.21                                                                      91.3 ± 1.57                                                                       90.6 ± 1.52                                                                       96.6 ± 2.39                         30  75.0 ± 2.62                                                                       77.6 ± 1.43                                                                       121.9 ± 6.17                                                                      93.3 ± 2.80                                                                       91.4 ± 6.20                                                                       94.8 ± 4.76                         60  75.1 ± 4.46                                                                       73.1 ± 4.08                                                                       125.2 ± 6.74                                                                      86.9 ± 6.14                                                                       90.9 ± 4.47                                                                       93.9 ± 3.98                         90  79.2 ± 4.56                                                                       87.0 ± 1.00                                                                       122.7 ± 1.32                                                                      84.6 ± 6.03                                                                       91.0 ± 3.34                                                                       104.3 ± 6.02                        130 73.8 ± 4.29                                                                       77.0 ± 3.96                                                                       134.5 ± 5.00                                                                      87.3 ± 4.44                                                                       94.9 ± 4.71                                                                       107.0 ± 3.44                        180 81.1 ± 1.34                                                                       84.9 ± 3.17                                                                       123.1 ± 4.46                                                                      87.5 ± 6.43                                                                       93.8 ± 6.49                                                                       109.3 ± 6.26                        __________________________________________________________________________    Meas-                                                                             Example 2            Example 5                                            ured                                                                              Rate of                                                                              Volume of                                                                            Expiration                                                                           Rate of                                                                              Volume of                                                                            Expiration                             time                                                                              breathing                                                                            breathing                                                                            /inspira-                                                                            breathing                                                                            breathing                                                                            /inspira-                              (min.)                                                                            (%)    (%)    tion (%)                                                                             (%)    (%)    tion (%)                               __________________________________________________________________________    Before                                                                        test                                                                              100.0 ± 0.00                                                                      100.0 ± 0.00                                                                      100.0 ± 0.00                                                                      100.0 ± 0.00                                                                      100.0 ± 0.00                                                                      100.0 ± 0.00                        1   120.8 ± 3.19                                                                      108.2 ± 1.78                                                                      78.4 ± 9.00                                                                       122.0 ± 16.99                                                                     100.5 ± 5.01                                                                      77.6 ± 3.68                         3   90.3 ± 3.36                                                                       86.7 ± 4.14                                                                       108.7 ± 11.36                                                                     93.7 ± 7.20                                                                       86.9 ± 5.99                                                                       92.3 ± 2.19                         6   92.2 ± 5.69                                                                       90.3 ± 8.26                                                                       99.8 ± 4.30                                                                       93.7 ± 5.80                                                                       86.4 ± 6.96                                                                       98.7 ± 3.93                         18  91.6 ± 5.71                                                                       86.0 ± 8.49                                                                       106.5 ± 5.25                                                                      99.9 ± 4.00                                                                       86.3 ± 3.71                                                                       97.7 ± 2.62                         30  96.4 ± 4.09                                                                       93.7 ± 3.75                                                                       100.3 ± 3.41                                                                      92.5 ± 1.76                                                                       86.6 ± 2.44                                                                       103.2 ± 1.10                        60  96.2 ± 3.62                                                                       96.6 ± 4.92                                                                       97.0 ± 3.47                                                                       97.0 ± 1.81                                                                       93.5 ± 6.17                                                                       94.3 ± 3.87                         90  94.0 ± 5.23                                                                       97.6 ± 7.12                                                                       96.5 ± 3.18                                                                       90.7 ± 6.14                                                                       93.5 ± 3.78                                                                       96.7 ± 4.58                         130 94.3 ± 6.97                                                                       92.1 ± 9.25                                                                       106.4 ± 4.19                                                                      92.9 ± 5.33                                                                       87.4 ± 3.03                                                                       106.2 ± 5.28                        180 98.2 ± 5.42                                                                       97.8 ± 7.28                                                                       108.7 ± 6.81                                                                      97.5 ± 1.82                                                                       95.1 ± 3.33                                                                       100.1 ± 2.03                        __________________________________________________________________________

In this experiment the control group exhibited such a pattern ofexpiratorydyspnea as encountered in a fit of a human asthma; i.e.immediately after the reaction induced, the rate and volume of breathingtransiently increased, followed by a steady decrease, and 3 minutesafter the reactioninduced, the ratio of expiration/inspirationincreased. By contrast, the animals administered with the compoundsaccording to the present inventionstrongly exhibited the inhibition onthe variation from the normal values exhibited in the control group,while the animals administered with2,4'-dimethyl-3-piperidinopropiophenone showed the less inhibitoryeffect than the compounds according to the present invention.

The compounds in Examples 2 and 5 were administered to rats toinvestigate inhibitory effect on homo PCA reaction. The results showedthat 5 mg/Kg ofintravenous administration of the former could inhibit62.1% of the reaction and 200 mg/Kg of peroral administration of thelatter could inhibit about 70% of the reaction (about 40% in the case ofperoral administration of the comparative compound, i.e.2,4'-dimethyl-3-piperidinopropiophenone); and their effects depended onthe dose.

The compounds according to the present invention are useful asanti-allergic agent for treatment of bronchial asthma, allergic rhinitisand allergic dermatitis. They can be administered singly or as combined,in appropriate forms of solid or liquid such as tablet, capsule, powder,ointment, aerosol, solution, suspension or emulsion. They are perorallyadministered as tablet, capsule, powder or aqueous solution, ornon-perorally adminstered as injection for subcutaneous, intravenous,intramuscular, intrarectal or intranasal, as liquid for dispersion oraerosol in the form of liquid or dry powder for application to themucosa of nose, throat or trachea, or as ointment.

For solid administration, tablet or capsule may be prepared bycombination of the compounds of the present invention with vehicle suchas lactose, mannite, corn starch, potato starch and other commonadditives; the bindersuch as crystalline cellulose, cellulosederivatives, gum arabic, corn starch and gelatine, the disintegratorsuch as corn starch, potato starch and carboxymethyl cellulose calciumand the lubricant such as talc and magnesium stearate; or they can beprepared as ointment in combination with the ointment base.

The compounds according to the present invention may also be prepared asaninjectable solution or an injectable suspension together with aphysiologically acceptable diluent, with or without adding asurface-active agent and other pharmaceutically acceptable assistants.Usually, distilled water for injection, physiological saline solution,aqueous solution of dextrose, vegetable oil for injection and glycolssuchas propylene glycol, polyethylene glycol are preferable liquiddiluents.

For aerosol administration, the compounds according to the presentinvention are charged into an aerosol vessel in the form of liquid orfineparticles, together with gaseous or liquid propellant, and, ifdesired, together with common assistants such as the wetting agent orthe dispersing agent. They may be prepared as a non-pressurized typesuch as the nebulizer or the atomizer.

The preferable dosage of the compounds according to the presentinvention depends on patient's condition and the manner ofadministration. Generallyspeaking, peroral adminstration of 0.1-100 mglevel of the compound per dayper one kg of the patient's body weightwould be desirable for the purpose of achieving the expected effect. Inthe general case of an adult a daily administration of 1 to 10 units ofa preparation containing 5-500 mg of the compound according to thepresent invention will suffice. Non-peroral daily administration, forexample, injection, of about 1/3-1/10 of the above dosage will haveapproximately the same effect. Daily administrationof 1 to 10 units of apreparation containing 0.5-170 mg of the compound according to thepresent invention is preferred.

Several prescription examples of pharmaceutical compositions containinga compound according to the present invention will be shown below.

    ______________________________________                                        Prescription Example 1 (tablet weighing 500 mg each)                          2-methyl-3-piperidino-β-                                                 propionaphthone hydrochloride                                                                          250    mg                                            Lactose                  190    mg                                            Crystalline cellulose    50     mg                                            Magnesium stearate       10     mg                                            Prescription Example 2 (capsule with 210 mg of filler)                        2,3',4'-trimethyl-3-piperidino-                                               propiophenone hydrochloride                                                                            10     mg                                            Magnesium stearate       5      mg                                            Lactose                  135    mg                                            Potato starch            50     mg                                            Talc                     10     mg                                            Prescription Example 3 (injection ampule with 1 ml capacity)                  2-methyl-3-dimethylamino-β-                                              propionaphthone hydrochloride                                                                      1.0% (by weight)                                         Solubilizer (used, if desired)                                                                     proper amount                                            Sodium chloride      "                                                        Distilled water for injection                                                                      "                                                                             Total 1 ml                                               Prescription Example 4 (ointment of 101 g in total weight)                    2-methyl-3-pyrrolidino-β-                                                propionaphthone hydrochloride                                                                          1      g                                             Emulsified wax           30     g                                             White vaseline           50     g                                             Liquid paraffin          20     g                                             Prescription Example 5 (suppository of 2 g in total weight)                   3',4'-dimethoxy-2-methyl-3-                                                   piperidinopropiophenone hydrochloride                                                                  10     mg                                            Cacao butter             1990   mg                                            Prescription Example 6 (aerosol)                                              2-methyl-3-morpholino-β-                                                 propionaphthone hydrochloride                                                                      5.0% (by weight)                                         Sorbitan trioleate   proper amount                                            Dichlorodifluoromethane                                                                            "                                                        Trichlorofluoromethane                                                                              "                                                                            Total 100% (by weight)                                   ______________________________________                                    

What is claimed is:
 1. A method for alleviating the appearance ofvarious allergic symptoms in the human body which comprisesadministering to the human body an effective amount of a compositioncomprising a carrier and a compound of the formula: ##STR3## in which:(a) when R₁ is hydrogen;A is β-naphthyl; naphthyl substituted bymethoxy; or phenyl substituted by two to five alkyls having each one tofour carbon atoms; and B is piperidino; (b) when R₁ is alkyl having oneto two carbon atoms; A is indanyl; tetrahydronaphthyl; naphthyl;naphthyl substituted by halogen, hydroxy, alkyl having one to fourcarbon atoms or alkoxy having one to four carbon atoms; phenylsubstituted by alkyl having one to ten carbon atoms, alkoxy having oneto four carbon atoms or phenyl; phenyl substituted by two to five alkylshaving each one to four carbon atoms; phenyl substituted by two to fivealkoxys having each one to four carbon atoms; phenyl substituted byalkoxy having one to four carbon atoms and halogen or hydroxy; or phenylsubstituted by two halogens; and B is dialkylamino having each one tofour carbon atoms; pyrrolidino; morpholino; piperidino; piperidinosubstituted by alkyl having one to four carbon atoms or benzyl; orpiperazino substituted by alkyl having one to four carbon atoms orbenzyl provided that; when A is phenyl substituted by one alkyl havingone to three carbon atoms or methoxy, B is the said group other thanpiperidino; or a pharmaceutically acceptable salt thereof.
 2. A methodaccording to claim 1 wherein said compound is4'-hexyl-2-methyl-3-piperidinopropiophenone.
 3. A method according toclaim 1 wherein said compound is selected from the group consisting of2-methyl-3-piperidino-β-propionaphthone,2-methyl-3-dimethylamino-β-propionaphthone,2-methyl-3-morpholino-β-propionaphthone,2-methyl-3-pyrrolidino-β-propionaphthone, 3-piperidino-β-propionaphthoneand 2-methyl-3-(4-benzylpiperidino)-β-propionaphthone.
 4. A methodaccording to claim 1 wherein said compound is selected from thegroupconsisting of4'-hydroxy-3'-methoxy-2-methyl-3-piperidinopropiophenone,2-methyl-3-piperidino-4'-phenylpropiophenone,2,2',4',6'-tetramethyl-3-piperidinopropiophenone,2,2',3',4',5',6'-hexamethyl-3-piperidinopropiophenone,4'-n-heptyl-2-methyl-3-piperidinopropiophenone,2-methyl-4'-n-octyl-3-piperidinopropiophenone,4'-n-decyl-2-methyl-3-piperidinopropiophenone, '-chloro-4'-methoxy-2-methyl-3-piperidinopropiophenone,3',4'-dichloro-2-methyl-3-piperidinopropiophenone,4'-n-butyl-2-methyl-3-piperidinopropiophenone,4'-isobutyl-2-methyl-3-piperidinopropiophenone and4'-tert-butyl-2-methyl-3-piperidinopropiophenone.
 5. A method accordingto claim 1 wherein said compound is selected from the groupconsisting of2-methyl-3-piperidino-α-propionaphthone,2-methyl-3-(2-methylpiperidino)-β-propionaphthone,2-methyl-3-(3-methylpiperidino)-β-propionaphthone,2-methyl-3-(4-methylpiperidino)-β-propionaphthone, and2-ethyl-3-piperidino-β-propionaphthone.
 6. A method according to claim 1wherein said compound is selected from the groupconsisting of6'-methoxy-3-piperidino-2'-propionaphthone,6'-methoxy-2-methyl-3-piperidino-2'-propionaphthone,1'-hydroxy-2-methyl-3-piperidino-2'-propionaphthone,2,6'-dimethyl-3-piperidino-2'-propionaphthone,6'-hydroxy-2-methyl-3-piperidino-2'-propionaphthone,6'-chloro-2-methyl-3-piperidino-2'-propionaphthone,6'-methoxy-2-methyl-3-dimethylamino-2'-propionaphthone and6'-methoxy-2-methyl-3-(4-methylpiperidino)-2'-propionaphthone.
 7. Amethod according to claim 1 wherein the allergic symptom is allergicdermatitis.
 8. A method according to claim 1 wherein the allergicsymptom is bronchial asthma.
 9. A method according to claim 1 whereinthe allergic symptom is allergic rhinitis.